Project Summary: Illness behaviors and metabolic disturbances are common in pancreatic cancer patients, and may lead to wasting or cachexia. This devastating state of malnutrition is brought about by a synergistic combination of a decrease in appetite and an increase in metabolism of fat and lean body mass. The severity of cachexia in many illnesses is the primary determining factor in both quality of life, and in eventual mortality. Other illness- induced morbidities including lethargy also compromise the ability of patients to recover from life-saving or extending interventions, and diminish the motivational drive to aggressively battle the condition. Although cachexia in cancer patients was described more than two thousand years ago, the central mechanisms underlying this disorder are poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. Our laboratory is dedicated to unraveling the basic neuroscience of cachexia. In this proposal, we will focus on understanding the scope and mechanism by which signals of pancreatic cancer development are received, amplified, and maintained by the hypothalamus. The significance of this proposal resides in its unique combination of our historical focus on neuroendocrinology and behavior, with new collaborations and efforts directed at understanding the role of extracellular vesicles in neuroinflammation. The long-term goal of our research is to gain mechanistic understanding of the acute illness response and how it is transitioned into chronic inflammation-associated cachexia in order to develop more effective therapeutic interventions.